An adenylyl cyclase exotoxin in complex with calmodulin

Edema factor (EF) is a calmodulin (CaM) activated adenylyl cyclase secreted by Bacillus anthracis. It is homologous to exotoxins from Pseudomonas Aeruginosa (ExoY) and Bordetella pertussis (CyaA). The crystal structure of the 58kDa enzymatic domain of EF in complex with CaM provides the first example of an intact enzyme using a large and structurally distributed binding surface to recognize CaM. Calmodulin adopts an extended conformation very different from previous structures of CaM collapsed around a helix or helices, seen in previous studies. EF surrounds CaM and 5800 A2 of surface area is buried between the proteins. The CaM C-terminus appears to be calcium loaded and the N-terminus calcium free. EF shares no structural homology with mammalian adenylyl cyclases (mAC). In the active site, 3′deoxy ATP and a single metal ion are well positioned for catalysis utilizing histidine 351 as a catalytic base. This observation is novel and different than the di-metal mediated mechanism proposed for mAC.